G protein-coupled receptors (GPCRs) superfamily is comprised of receptors involved in the detection of a wide range of chemicals, including nutrients, hormones and neurotransmitters. GPR40 and GPR120, also known as free fatty acid receptors 1 and 4 (FFA1-4), are both activated by medium- and long-chain saturated and unsaturated fatty acids derived from dietary triglycerides [Hudson B. D. et al., Adv Pharmacol (2011), 62: p. 175-218]. In humans and rodents GPR40 was initially shown to be expressed in different regions of brain and in pancreatic beta cell [Briscoe C. P. et al., J Biol Chem (2003), 278(13): p. 11303-11] where GPR40 activation leads to increased intracellular calcium levels and consequent insulin secretion. GPR40 is also expressed by gut enteroendocrine cells [Edfalk, S. et al., Diabetes (2008), 57(9): p. 2280-7; Liou A. P. et al., Gastroenterology (2011), 140(3): p. 903-12] where the receptor is activated by fatty acids, generating the release of incretin hormones such as glucagon-like peptide-1 (GLP-1). GPR120 is highly expressed in the intestine (enteroendocrine L cell of the colon and cell lines such as STC-1), but also in the lung, thymus, spleen, and pancreas [Hirasawa A. et al., Nat Med (2005), 11(1): p. 90-4; Taneera J. et al., Cell Metab (2012), 16(1): p. 122-34; Tanaka T. et al., Naunyn Schmiedebergs Arch Pharmacol (2008), 377(4-6): p. 523-7].
As for GPR40, activation of GPR120 on enteroendocrine cells contributes to the increase of intracellular calcium levels causing secretion of GLP-1.
GLP-1 is a gut-derived peptide secreted from intestinal L-cells after a meal. GLP-1 exerts profound effects in the regulation of glycaemia, stimulating glucose-dependent insulin secretion, pro-insulin gene expression and beta-cell proliferative pathways [Drucker D. J., Cell Metab (2006), 3(3): p. 153-65]. GLP-1 secretion is reduced in patients with type 2 diabetes, and this may contribute in part to the hyperglycaemia observed in these individuals [Mannucci E. et al., Diabet Med (2000), 17(10): p. 713-9]. The confirmed success of GLP-1 to lower glycaemia has led to approval of the GLP-1 receptor agonist exendin-4 (Byetta) and Liraglutide (Victoza) as well as inhibitors of the GLP-1 peptidase Dipeptidyl-peptisase-4 (DPP-4), for the treatment of patients with type 2 diabetes (T2D).
At least initially, individuals affected by T2D do not need insulin treatment since beta cells compensate by increasing their insulin production. As the disease progress, the compensatory response fails in producing insulin and maintaining normal glucose levels leading the patient to the need of a pharmaceutical treatment.
Current treatments that target either insulin resistance (metformin, thiazolidinediones) or insulin release from beta cells (sulphoylureas, exanatide) were associated to the risk of developing hypoglycaemia. Therefore, treatments based on glucose-dependent mechanisms of action to induce insulin secretion from beta-cells are needed.
Selective activation of GPR-40 and/or GPR-120 may provide potential therapeutic benefit to treat T2D and its associated conditions with minimal risk of hypoglycaemia. GPR120 is also expressed in adipocytes playing an important role in differentiation and maturation. Increased mRNA levels during adipocyte differentiation was described in in vitro models of adipogenesis as well as in human adipose tissue [Gotoh C. et al., Biochem Biophys Res Commun (2007), 354(2): p 591-7]. It was shown that GPR120 expression in human adipose tissue was significantly higher in obese individuals than controls, suggesting that the expression of GPR120 could be enhanced by the accumulation of dietary lipids. The same study revealed that GPR120-deficient HFD mice developed obesity [Ichimura A. et al., Nature (2012), 483(7389): p 350-4]. These data show that GPR120 acts as a lipid sensor and suppression of lipolysis by a GPR120 agonist would decrease the concentration of FFAs in blood, normalizing lipid levels and indeed leading to improvement in insulin resistance.
Based on clinical studies, that correlated body fat mass with lower bone density and increased fracture risk, lipids were thought to have a direct action on bone. The effects of GPR120/40 agonists were therefore tested as therapeutic molecules in bone metabolism regulation [Cornish J. et al., Endocrinology (2008), 149(11): p 5688-95].
Finally, it has been shown that GPR120 on macrophages can be activated by omega-3 fatty acids for the repression of inflammatory cytokine release. GPR120 anti-inflammatory effects are mediated by β-arrestin signalling [Oh D. Y. et al., Cell (2010), 142: p 687-98]. In vivo experiments on obese mice treated with an orally available GPR120 agonist, demonstrated the potent anti-inflammatory effects of GPR120 activation and the consequent improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis [Oh D. Y. et al., Nat Med (2014), 20: p 942-7].
WO2014/073904 discloses a novel compound having GPR40 receptor agonist activity that promotes insulin secretion and inhibits blood sugar rise after glucose loading, and is thereby useful for the treatment of diabetes and complications thereof, the preparation method thereof and pharmaceutical composition containing them as an active ingredient.
WO2014/209034 discloses novel biaryl derivatives as GPR120 agonists, a method for preparing the same, a pharmaceutical composition comprising the same as active components and use thereof for preventing or treating diabetes, complications of diabetes, obesity, non-alcoholic fatty liver, steatohepatitis, osteoporosis or inflammation.
US2011184031 discloses a novel phenyl compound, particularly an aralkylcarboxylic acid compound, having an agonistic activity for GPR120 and/or GPR40.
WO2016/057731 relates to novel compounds which are GPR40 agonists for the treatment of various diseases, syndromes and disorders, including Type II diabetes mellitus, obesity, obesity-related disorders, impaired glucose tolerance, insulin resistance, metabolic syndrome, other cardiovascular risk factors such as hypertension and cardiovascular risk factors related to unmanaged cholesterol and/or lipid levels, osteoporosis, inflammation and eczema.
US20150274672 reports compounds as GPR120 modulators for the treatment and/or prevention of diabetes, obesity, hyperlipidaemia, inflammation and related disorders.